Basic ethers of hydroxyethylpiperazinopropylphenothiazines



United States Patent ware No Drawing. Filed Feb. 28, 1963, Ser. No. 261,866 Claims. (Cl. 260-243) This invention relates to new ethers of phenothiazines having valuable therapeutic properties, and processes for the preparation thereof.

The new therapeutically active compounds of this invention include phenothiazines of the general formula:

and non-toxic acid-addition salts thereof; wherein r is 1 or 2; X is hydrogen, halogen (preferably chloro), trifiuoromethyl, lower alkyl, lower alkoxy, lower alkanoyl, lower alkyl mercapto, trifiuoromethylmercapto trifiuoromethoxy, N,N-dimethylam'inosulfonyl and lower alkylsulfonyl (preferably methylsulfonyl); A is a lower alkylene radical of at least two carbon atoms; and NB is a basic saturated nitrogen-containing radical of less than seventeen carbon atoms. Among the suitable radicals represented by the symbol NB are: amino;

(lower alkyl)amino;

di(lower alkyl)amino;

(hydroxy-lower alkyl) amino;

di-(hydroxy-lower alkyl) amino;

and basic saturated 5 to 7 membered monocyclic N- heterocyclic radicals of less than seventeen carbon atoms, as exemplified by piperidino; (lower aIkyDpiperidino [e.g., 2, 3 or 4-(lower alkyl) piperidino] di(lower alkyl)piperidino[e.g., 2,4-, 2,5- or 3,5-di(lower alkyl)-piperidino] (lower alkoxy)piperidino; homopiperidino;

pyrrolidino;

(lower alkyl) pyrrolidino; di(lower alkyl)-pyrrolidino; (lower alkoxy)pyrrolidino; morpholino;

(lower alkyl)rnorpholino;

di (lower alkyl morpholino; (lower alkoxy) morpholino; thiamorpholino;

(lower alkyl)-thiamorpholino; di(lower alkyl)thiarnorpholino; (lower alkoxy)thiamorpholino; piperazino;

(lower alky1)piper=azino (e.g., N -methylpiperazino);

.di(lower alkyl)piperazino;

(lower alkoxy)piperazino;

(hydroxyl-lower alkyl)-piperazino [e.g., N -(2-hydroxyethyl piperazino] (alkanoyloxy-lower alkyl)piperazino [e.g., N -(2-acetoxyethyl)piperazino and N (Z-heptanoyloxyethyl piperazino] (hydroxy-lo'wer alkoxy-lower alkyl)piperazino [e.g., N

(2-hydroxyethyl) piperazino] (alkenoyloxy-lower alkyl)piperazino [e.g., N -(2- undecylenoyloxyethyl piperazino] Patented August 2, 1966 (carbo-lower a1koxy)piperazino [e.g., N -(2-carbornethoXy, carboethoxy or carbopropoxy)piperazino];

homopiperazino; and

N lower =alkyl)homopiperazino (e.g., N -methylhomopiperazino The terms lower alkyl, lower alkoxy and lower alkylene, as employed herein, include both straight and branched chain radicals of less than eight carbon atoms. The particularly preferred compounds are those wherein A is a lower alkylene radical of two to three carbon atoms (e.g., ethylene, trimethylene 1,3 and propylene-1,2); NB represents a di(1ower alkyl)-amino radical; r is one and X is chloro or trifluoromethyl.

As to salts of the bases of this invention, those coming within the purview of this invention include the acid-addition salts, particularly, the non-toxic acid-addition salts. Acids useful for preparing the acid-addition salts, include, inter alia, inorganic acids, such as the hydrohalic acids (e.g., hydrochloric and hydrobrornic acid), sulfuric acid, nitric acid and phosphoric acid, and organic acids, such as oxalic, maleic, fumaric, tartaric, citric, acetic, succinic and pamoic acid.

The compounds of this invention are therapeutially active compounds which are utilizable both as tranquilizing (ataractic) agents, and thus may be used in the treatment of depressed psychotic states, and as antihistamines. For these purposes they may be administered orally or parenterally in conventional dosage forms such as tablets, capsules, injectables or the like by incorporating the appropriate dose of the compound with carriers according to accepted pharmaceutical practice. The compounds of this invention are superior to known phenothiazine tranquilizing agents in that they possess an antagonism to the extrapyramidal syndrome, a side-effect frequently associated with therapy by these agents.

The compounds of this invention can be prepared by interacting a compound of the general Formula I:

m CHZCHICHz-N N- ornomm-H wherein X and r are as hereinbefore defined, with an aminoalkyl halide (preferably aminoalkyl chloride) of the formula: Y-A-NB, wherein Y is halo and A and NB are as hereinbefore defined, the reaction preferably being conducted in an organic solvent, benzene, toluene or tetrahydrofuran for the reactants in the presence of a basic compound, such as sodium hydride. Among the suitable phenothiazine reactants may be mentioned:

10- E 3 -(2-hydroxyethy1)piperazinopropyl] phenothiazine;

10- 3 Z-hydroxyethyl piperazinopropyl] -2-halophenothiazines, such as 10- 3-( 2-hydroxyethyl) piperazinopropyl] -2-chlorophenothiazine;

10- [3 Z-hydroxyethyl) piperazinopropyl] -2-trifluoromethylphenothiazine;

l0- [3 2-hydroxyethoxyethyl -piperazinopropyl] -2-halophenothiazines, such as 10- [3 Z-hydroxyethoxyethyl piperazinopropyl-Z- chlorophenothiazine;

10-[3 Z-hydroxyethoxyethyl piperazinopropyl] -2- (trifiuoromethyl phenothiazine;

10- 3- 2-hydroxyethyl piperazinopropyl] -2-( lower alkyl -phenothiazines, such as 10- [3- (Z-hydroxyethyl) piperazinopropyl] -2- methylphenothiazine;

- [3-( 2-hydroxyethyl)piperazinopropyl] -2-(lower alkoxy).phenothiazines, such as 10-[3-(2-hydr'oxyethyl) piperazinopropyl] -2- methoxyphenothiazine;

10- [3-(2-hydroxyethyl) piperazinopropyl]-2-(lower alkanoyl)phenothiazines, such as 10-[ 3 (2-hydroxyethyl) piperazinopropyl] -2-propionylphenothiazine;

10- [3-(2-hydroxyethyl.) piperazinopropyl] -2-(1ower alkyl mercapto)-phenothiazines, such as 10-[3-(2-hydroxyethyl) piperazinopropyl] -2-methylmercaptophenothiazine;

10 [3 (Z-hydroxyethyl) -piperazinopropyl] -2-triflu'oro- V methylmercaptophenothiazine;

10- [3- 2-hydroxyethyl piperazino propyl] -2-trifluoro- 'methoxyphenothiazine;

1Q-[3-(2-hydroxyetl1y1)piperazinopropyl] -2-methylsulfonylphenothiazine and I 10- [3 Z-hydroxyethyl piperazinopropyl] -2-N,N-

dimethylaminosulfonylphenothiazine.

Alternatively, the compounds of this invention can be prepared by interacting a compound of the General Formula II:

wherein:X and r are as hereinbefore defined and Z:is halogen, preferably chlorine or bromine, With'an amino alcohol of the formula: HO-ANB, wherein A and NB are as hereinbefore defined, in the presence of a condensing agent such as sodium hydride, in an=organic solvent,

.such as toluene or t'etrahydrofuran. The compounds: of

Formula II can be prepared as disclosed inapplic-ation, Serial No. 254,459, filed January 28, 1963, now Patent No. 3,194,733, granted July 13, 1965, by interacting a compound of Formula I with a thionyl halide such as thionyl chloride and thionyl bromide.

Among the suitable phenothiazine reactants of the Formula II may be mentioned:

10-[3 (2 chloroethyl)piperazinopropyl]-2-(lower alkoxy) phenothiazines, such as 10- [3 2-chloroethyl) piperazinopropyl] -2-methoxyphenothiazine;

10- [3- (2-chloroethyl piperazinopropyl] -2- (lower alkanoyl)phenothiazines, such as 10- [3 2-chloroethyl) piperazinopropyl] -2-propionylphenothiazine;

10- [3 (Z-chloroethyl) -piperazinopropyl] -2- (lower alkyl I,

mercapto)phenothiazines, such as 10 3- 2-chloro'ethyl piperazinopropyl] -2-rnethylmercaptophenothiazine;

10- [3 2-chloroethyl piperazinopropyl] -2-trifiuoromethylmercaptopheno thiazine;

4.. V 10- [3 -(2-chloroethyl) piperazinopropyl] -2-trifluoromethoxyphenothia'zine; 10- [3 2-chloroethyl) piperazinopropyl] -2-methylsulfonylphenothiazine and 10-[3-(2 -ch1oroethyl) piperazinopropyl] -2-N;N-dimethylaminosulfonylphenothiazine.

The compoundsof this'invention can also be prepared by interacting a compound of the Formula II; with an alkali metal amin'oalcoholate of. the general. formula: MOA-NB, wherein A and NB are as hereinbefore defined and M is sodium or potassium,'in an organic solvent, such as toluene or tetrahydrofuran.

In addition, the. compounds of this. invention can be prepared by first interacting a compound of the general Formula II with a halo-lower alkanol to give a compound of the general Formula IIIz' (III) wherein X; r,. A and Z are as hereinbefore defined, and

then interacting a compound of the general Formula III with .a compoundiof the general structure: HNB, wherein NB is as hereinbefore defined.

The compounds of this invention can also. be prepared by interacting a compoundof the, general Formula IV:

wherein is as hereinbefore defined, witha compound of the general formula: Z'(CH CH Q),A-NB, wherein Z, r, A and NB are as hereinbefore defined,-in an organic solvent, such as benzene, toluene, methyl ethyl ketone or tetrahydrofuran in'the presence of a basic compound, such as barium hydroxide;

The free bases of this invention can be converted to acid-additionrsalts by treatment with the desired acid.

This reaction is preferably conducted in an inert organic solvent under substantially anhydrous conditions by treat ing' the base with the acid, whereby the acid-addition. salt is formed.

The following examples illustrate the invention (all i temperatures being in centigrade):

EXAMPLE; 1

4-{3 [2-( trifluoromethyl) phenothiazine-Z O-yl] pr0pyl}- piperazinoethyl Z-dimethylaminoethyl ether (a) Preparation of 4-{3-[2-,(trifluoromethyl)phenothiaZine-ZO-yl]propyl}-piperazinbethyl Z-dimethyIaminOethyZ ether, hydrochloride salt.- To 32.8

propyl}piperazinoethanol in 125 ml. of dry toluene is added slowly 3.55 gof a 50% dispersion of sodium'hydride in min'eraloil.

Following the-vigorous reaction,- the mixture is refluxed j for an hour, cooled and treated with 8.0 g. of freshly distilled Z-dimethylaminoethyl chloride. Subsequently',.the mixture is heated at for 16 hours, cooled and filtered. The filtrate :is washed withwater :and ?then with 10% aqueous hydrochloric ,acid. The aqueous hydrochloric acid extract is cooled to:0 to yield the t-rihydrochloride salt.

(b) Preparation of the free base.-The. trihydrochloride obtained in step *a is: added with cooling to an excess of 40% aqueous potassiumhydroxide, and the liberated oil extracted into ether. The ether extracts are concentrated to give 4-{3-[2-(trifiuoromethyl)phenothiazinee10- yl]propyl}piperazinoethy1 Z-dimethylaminoethyl ether as a pale yellow oil.

EXAMPLE 2 4- [3- (Z-chlorophenoth ittzin-I O-yl) propyl] piperazinoethyl Z-dimethylaminoethyl ether Following the procedure of Example 1 but substituting an equivalent amount of 4-[3-(2-ch:lorophenothiazin-10- yl)propyl]piperazinoethanol for the pipenazinoethanol used in the example, 4-[3- (2-chlorophenothiazin-1O-yl) propyllpiperazinoethyl 2-dimethylaminoethyl ether is formed.

EXAMPLE 3 4- [3-(phenothiazin-IO-yl) prpyl]piperazin0ethyl Z-dimethylaminoethyl ether the indicated 2-subst-itute-d phenothiazine ether is formed:

Example Starting Material Product Formed Q-dimethylarninoethyl ether 4 4-[3 (Z-methylphenothiazin- 4-[3-(2-methylphenothiazin- 10-yl)-propyl]piperazino- 10-yl)propyl]piperazinoethanol. ethyl.

5 4-[3-(2-methoxyphenothi- 4-[3-(Q-methoxyphenothiazin--yl)propyl]piperazin-lO-yDpropylpiperazinoethanol. aziuoethyl.

6 4-[3-(Z-propionylphenothi- 4 [3-(2 propionylphenothiazm-10-yl)propyl]piperazin-10-yl)propyl]piperazinoethanol. azinoethyl.

7 4-{3'[2r(methy1mercapt0) 4-{3-[2-(methylmercapto) phenothiazin-lO-yflprophenothiazin-l0-yl1propyl )prperazmoethanol. pyl Ipiperazinoethyl.

8 4-{3-[2-(tr1fiuoromethyl- 4-(3-[2-(trifluoromethylmercapto)-phen0thiazinmereapto) -phenothiazin- 10-yl1propyl l-piperazinolo-yqpropyl -piperazinoethanol. ethy 9 4-{3-[2-(triiiuoromethoxy) 4-{3-[2-(trifluoromethoxy) phenoth1az1n-10-y1]prophenothiazin-lO-yljpropyl )prperazinoethanol. pyl )piperazinoethyl.

l0 4-{3-[2-(methylsulf0nyl) 4-{3-[2-(methylsulionyD- phenothmzm-lO-yflprophenothiaziirlO-yflpropyl piperazinoethanol. pyl lpiperazinoethyl.

11 4-{3-[2-(N,N-d1methyl arni- 4-(3-[2-(N,N-dimethylaminosulfonyhphenothiazinnosulfonyl)phenothiazin- 1O-y1]pr0pyl}p1peraz1no- 10-y1]pr0pyl}piperazinoethanol. ethyl.

EXAMPLE 12 4-{3-[2-( trifluoromethyl) phenothiazin-l O-yl] pr0pyl}- piperazinoethoxyethyl Z-dimethylaminoethyl ether Following the procedure of Example 1 but substituting an equivalent amount of 4-{3-[2-(ltrifluo-romethyl)phenoth-iazin-l0-yl]propyl}-piperazinoethoxyeth anol for the piperazinoethanol used in the example, 4-{3-[2-(trifluoromethyl)phenothiazin l0-yl]propyl} piperazino-ethoxyethyl Z-dimethylaminoethyl ether is formed.

EXAMPLE 13 4 {3 [2-(trifluoromethyl)p lzenothiazin-l0-yl]pr0pyl}- piperzzzinoethyl Z-dimethylaminoethyl ether, trima lea te salt A solution of 32.6 g. of the pale yellow oil obtained in Example lb in 225 ml. of warm 'acetonitrile and 22.5 g. of maleic acid in 225 :ml. of boiling acetonitr-ile are combined with vigorous stirring. The clear solution is allowed to cool slowly, then cooled in ice, and the solid filtered. The dried solid is recrystallized from isopropanol to give about 46 g. of 4-{3-[2-(trifluoromethyl)p-henothiazin-lO-yl]p-ropyl}-piperazinoethyl Z-dimethylaminoethyl ether, trimaleate salt, M.P. about 143.

6 EXAMPLE 14 4-{3- [2-( trifluoromethyl) phenothiazin-l O-yl] pr0pyl}- piperazinoethyl 3-piperidin0pr0pyl ether Following the procedure of Example 1 but substituting an equivalent amount of 3piperidinopropyl chloride for the Z-dimethylaminoethyl chloride, 4-{3-[2-(trifluoromethyl) phenothiazin-l O-yl ]p-ropyl}-piperazinoethyl 3-piperidinopropyl ether is obtained.

EXAMPLE 15 4-{3- [2-( trifluoromethyl) phenothiaz'in-l O-yl] pr0pyl}- V piperazinoethyl 3-methylamin0pr0pyl ether Following the procedure of Example 1 but substituting .an equivalent amount of 3-methyrlaminopropyl chloride for the 2-dimethyl-aminoethyl chloride, 4-{3-[2-(trifluoromethyDphenothiazin 10-yl]-propyl}-piperazinoethyl 3- methylaminopropy-l ether is obtained.

EXAMPLE 16 4-{3- [2- trifluoromethyl phenothiazz'n-l O-yl] prowl}- pi perazinoethyl 3-(N -methylp'iperazin0) propyl ether Following the procedure of Example 1 but substituting an equivalent amount of 3-(N -methylpiperazino)propyl chloride for the 2-dimethylaminoethyl chloride, [there is obtained 4-{3-[2-(trifiuoromethyl)-pl1enothiazin-l0-yl] propyl}-piperazinoethyl 3-(N -methylpi-perazino)-propyl ether.

In a similar manner, by substituting the indicated aminoalkyl chloride for the Z-dimethylarninoethyl chloride in the procedure of Example 1, the indicated ether of 4-{3-[ 2- (-trifluoromethyl)phenothiazin 10-yl]propyl}piperazinoethyl 1s obtamed:

Example Starting Material Ether Formed 17 2-(2-hydr0xyethyl)aminoethyl 2-(2-lrydroxyethyl) chloride (prepared from Z-amiammoethyl. noethanol and ethylene chlorobromide).

18 4-di(2-hydroxyethyl)aminobutyl 4-d1(2-hydroxyethyl) chloride (prepared from diethaaminobutyl. nolamine and tetra-methylene chlorobromide) 19 3-morpholinopropyl chloride 3-morpl1ol1nopropyl.

20 2-homopiperidinoethyl chloridem, 2-hglmtipiperidmo- 21 3-(N -ethylhomopiperazino)pro- 3-(N -ethylh0mopiperpyl chloride (prepared from N azino)propy1. ethylhomopiperazine and trimethylene chlorobromide). 4

22 5-thiamorph0linopentyl chloride 5-th1amorphohnopen- (prepared from thiarnorpholine tyl. and pentamethylene chlorobromide).

23 Z-diethylaminoethyl chloride 2-diethylaminoethyl.

24 2-(N-methyLN-isopropylamino) Z-(N-methyl-N-isoproethyl chloride. pyl-amm0)ethyl.

EXAMPLE 25 4 {3 [2 (trifluoromethyl)phenothiazin 1 0 yl]pr0- pyl} pipemzinoethyl 3 {N [2 (heptanoyloxy) ethyl] piperazin0}pr0pyl ether (3.) Preparation 0] Z-bromoethyl hep tanoate.To 125 g. of 2-bromoethanol in 500 ml. of dry chloroform is added dropwise, 148.5 g. of heptanoyl chloride. Subsequently the mixture is refluxed for four hours and the chloroform distilled to give 2-bromoethyl heptanoate.

(b) Preparation of N -[Z-(heptanoyloxy)ethyl]piperazine.--To 17.6 g. of anhydrous piperazine, 13.8 .g. of anhydrous potassium carbonate and 250 ml. of anhydrous methyl ethyl ketone is added dropwise and with stirring 23.7 g. of 2-bromoethyl heptanoate. Subsequently, the mixture is stirred and refluxed for sixteen hours, the solvent is distilled, and the residue dissolved in ml. of

7 water. The solution is cooled, excess 20% aqueous hydrochloric acid added and the mixture extracted with ether. The aqueous solution is neutralized saturated with sodium chloride and extracted with ether. The ether extracts are dried and concentrated to give N -[2-(heptanoyloxy) ethyl1-piperazine.

Preparation of 3-{N [2-(heptanoyloxy)ethyl] piperazin0}propanol.-To 24.2 g. of N -[2-(heptanoyloxy)ethyl]piperazine is added 100 ml. of anhydrous ben-. zene, 17.1 g. of anhydrous barium hydroxide and 13.9v g. of 3-bromopropanol and the mixture stirred and refluxed for eighteen hours. The mixture is cooled, filtered and thebenzene distilled to give 3-{N -[2-(heptanoyloxy) ethyl] piperazino}propanol.

(d) Preparation of 4-{3-[2-(triflu0r0methyl)phenapyl}piperazinoethanol in 250 ml. of dry benzene is added 5 7.1 g. of thionyl chloride. The mixture .is kept overnight,

The precipitated solid is filtered and recrystallized fromabsolutew ethanol-anhydrous ether to give 10.4 g..of 4-{3-[2-(t.ri-

heated for three hours under reflux, cooled and treated with an excess of ethereal hydrogen chloride.

fluoromethyhphenothiazin 10 yl]pro-pyl}piper.aZino-. ethyl chloride as the dihydrochloride salt, M.P. 224-225 (dec.).

(e) Preparation of 4-{3-[2-(triflu0r0methyl)phenothia azin 10 ylJprapyl} piperazinoethyl 3 {N [Z-(heptan0yloxy)ethyl]-piperazimo}pr0pyl ether.-To 9.05 g. of 4 {3 [2 (trifluoromethyl)phenothiazin 10 yl]-propyl}piperazino ethyl chloride isadded 6.0 g. of the product from (c), 50 ml. of dry benzene and 3.42 'g. of anhydrous barium hydroxide. The mixture is stirred and refluxed for. eighteen hours to give v4-{3-[2-(trifluoromethyDphenothiazin-lO-yl] propyl}-piperazinoethyl 3-{N [2-heptanoyloxy)ethyl]piperazino}propyl ether.

Similarly, by substituting in Example c, equivalent amounts of 2-hydroxyethylpiperazine' or Z-(hydroxyethoxy)ethylpiperazine for the N [2-heptanoyloxy)ethyl]p ip erazine, there are obtained i3-{N [2-(hydroxyethyl)] piperazino}propanol and. 3-{N -[2-(hydr0xyethoxy) ethyl] piperazino}propanol, respectively.

Similarly, by substituting in Example25e, equivalent amounts of 3-{N -[2-hydroxyethy1) ]piperazino}propanol' 3-{N [2- (hydroxyethoxy ethyl] piperaziho}p'ropanol for the 3-.{N -[2-heptanoyloxy)ethyl]piperazin=o}propa-' nol,.there are obtained 4-{3-[2-(trifluoromethyl)phenow ethyl)]piperazino}propyl ether and 4-{3-[2-trifluoromethyl)phenothiazin 10 yl]propyl}piperazinopropyl 3-{N -[2-(hydroxyethoxy)ethyl]piperazin0}propyl ether, respectively.

8 This invention may=be variously otherwise embodied within the scope of the. appended claims.

What is claimed is:

LEAcompoundselected from, the groupconsisting of bases of the formula wherein :r is a positive integer less thanthree, A is lower alkylene. of at least two carbon atoms, NB is selected from the group consisting of amino, (loweralkyDamino, di(lower alkyl)amino, (hydroxy-lower alkyl)amino, di- (hydroxy-lower :alkyl)amino,' and basic saturated 5 to ,7 membered monocyclic N-heterocyclic radicals of less than seventeen carbon atoms, and Xis selected from the group 4.?Anon-toxic acid-addition salt of the compound of clainn'3.

5.-Thehydrochloridesalt of the compound of claim 3;

6. 4 [3 (2 F chlorophe'nothiazingl0 yl)propyl] piperazinoethyl 2-di(l-oweralkyl) amino(lower' alkyl) ether.

7.24 [3 (2 '--chloropl 1enothiazin 10 yl)propyl] piperazinoethyl Z-dimethylaminoethyl ether. I

8. A non-toxic acid-addition saltmf the compound of claim 2.

9. A non-toxic acid-addition saltlof the compound of;

'claim 6. e

10: A non-toxieacid-addition ,salt of the compoundof claim 7.?

References (Iited by the Examiner- UNITED STATES PATENTS 2,979,502 4/196l Gailliot'et al. .26024'3 FOREIGN' PATENTS 824,598 12/1959 Great Britain.

JOHN D. RANDOLPH; Primary Examiner. 

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF BASES OF THE FORMULA 